TIZANIDINE HYDROCHLORIDE

Tizanidine capsules contains tizanidine hydrochloride as the active ingredient, which is a central alpha 2 -adrenergic agonist. Its chemical name is 5-chloro-4-(2-imidazolin-2-ylamino)-2,1,3-benzothiadiazole monohydrochloride. It has a molecular formula of C 9 H 8 ClN 5 S-HCl and a molecular weight of 290.2. Its structural formula is: Tizanidine Hydrochloride is a white to slightly yellow crystalline powder. Tizanidine Hydrochloride is soluble in water and methanol. Tizanidine capsule are for oral administration and contains 2 mg or 4 mg or 6 mg tizanidine (equivalent to 2.29 mg or 4.58 mg or 6.87 mg tizanidine hydrochloride, respectively), the inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose monohydrate, microcrystalline cellulose and stearic acid. Each capsule shell contains fd & c blue # 1, fd & c red # 3, gelatin and titanium dioxide. The 2 mg capsule is printed with black pharmaceutical ink which contains black iron oxide, potassium hydroxide and shellac; 4 mg and 6 mg capsule is printed with white pharmaceutical ink which contains potassium hydroxide, shellac and titanium dioxide. figure

Tizanidine capsules are a central alpha-2-adrenergic agonist indicated for the treatment of spasticity. ( 1 ) Tizanidine capsules are indicated for the treatment of spasticity in adults.

Monitoring of aminotransferase levels is recommended at baseline and 1 month after maximum dose is achieved. ( 2.1 ) Recommended starting dose: 2 mg by mouth every 6 to 8 hours, as needed, up to a maximum of 3 doses in 24 hours ( 2.2 ) Dosage can be increased by 2 mg to 4 mg per dose every 1 to 4 days; maximum total daily dosage is 36 mg ( 2.2 ) Tizanidine pharmacokinetics differs between tablets and capsules, and when taken with or without food. These differences could result in a change in tolerability and control of symptoms. Consistent administration with respect to food is recommended. If substitution between dosage forms is necessary, take into consideration these pharmacokinetic differences. ( 2.2 , 2.6 , 12.3 ) Patients with renal impairment (creatinine clearance <25 mL/min) or hepatic impairment: use lower individual doses during titration. If higher doses are required, individual doses rather than dosing frequency should be increased. ( 2.3 , 2.4 ) To discontinue tizanidine hydrochloride, decrease dose slowly to minimize the risk of withdrawal adverse reactions ( 2.5 ) 2.1 Recommended Evaluation and Testing Before and After Initiating Tizanidine Capsules Monitoring of aminotransferase levels is recommended at baseline and 1 month after maximum dose is achieved [see Warnings and Precautions (5.2) ]. 2.2 Recommended Dosage The recommended starting dose is 2 mg by mouth every 6 to 8 hours, as needed, to a maximum of three doses in 24 hours. Dosage can be gradually increased every 1 to 4 days by 2 mg to 4 mg at each dose based on clinical response and tolerability. The maximum total daily dosage is 36 mg. Single doses greater than 16 mg have not been studied. There are pharmacokinetic differences when administering tizanidine hydrochloride between the fed or fasted state [see Clinical Pharmacology (12.3) ]. Tizanidine capsules may be taken with or without food; however, consistent administration with respect to food is recommended to reduce variability in tizanidine plasma exposure . Because of the short duration of therapeutic effect, treatment with tizanidine hydrochloride should be reserved for those daily activities and times when relief of spasticity is most important. 2.3 Recommended Dosage in Patients with Renal Impairment In patients with creatinine clearance <25 mL/min, use lower individual doses during titration. If higher doses are required, the individual doses rather than dosing frequency should be increased [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . 2.4 Recommended Dosage in Patients with Hepatic Impairment In patients with hepatic impairment, use lower individual doses during titration. If higher doses are required, individual doses rather than dosing frequency should be increased [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ]. 2.5 Discontinuation of Tizanidine Capsules When discontinuing tizanidine capsules, particularly in patients who have been receiving high doses for long periods or who may be on concomitant treatment with narcotics, decrease the dosage by 2 mg to 4 mg per day to minimize the risk of withdrawal adverse reactions [see Drug Abuse and Dependence (9.3) ]. 2.6 Switching Between with/without Food and Different Tizanidine Dosage There are pharmacokinetic differences when: 1) switching between administration of tizanidine capsules with or without food 2) switching between dosage forms if being administered with food . If these situations occur, monitor patients for therapeutic effect or adverse reactions [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)

Concomitant use with strong CYP1A2 inhibitors ( 4 , 7.1 ) Patients with a history of hypersensitivity to tizanidine or the ingredients in tizanidine capsules ( 4 , 5.5 ) Tizanidine capsules are contraindicated in patients: taking strong CYP1A2inhibitors [see Drug Interactions (7.1) ] . with a history of hypersensitivity to tizanidine or the ingredients in tizanidine capsules. Symptoms have included anaphylaxis and angioedema [see Warnings and Precautions (5.5) ].

The most common adverse reactions (greater than 10% of patients taking tizanidine and greater than in patients taking placebo) were dry mouth, somnolence, asthenia, and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals USA Inc. at 1-877-993-8779, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following clinically significant adverse reactions are described elsewhere in other sections of the prescribing information: Hypotension [ see Warnings and Precautions (5.1) ] Liver Injury [ see Warnings and Precautions (5.2) ] Sedation [ see Warnings and Precautions (5.3) ] Hallucinosis/Psychotic-Like Symptoms [ see Warnings and Precautions (5.4) ] Hypersensitivity Reactions [see Warnings and Precautions ( 5.5 )] Withdrawal Adverse Reactions [see Warnings and Precautions (5.6 )] 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. The safety of tizanidine has been evaluated in three double-blind, randomized, placebo-controlled clinical studies [see Clinical Studies (14) ] . Two studies were conducted in patients with multiple sclerosis and one in patients with spinal cord injury. Each study had a 13-week active treatment period which included a 3-week titration phase to the maximum tolerated dose up to 36 mg/day in three divided doses, a 9-week plateau phase where the dose of tizanidine was held constant and a 1-week dose tapering period. In all, 264 patients received tizanidine and 261 patients received placebo. Across the three studies approximately 51% of patients were women, and the median dose during the plateau phase ranged from 20 to 28 mg/day. The most common adverse reactions (>10% of patients treated with tizanidine) reported in multiple dose, placebo-controlled clinical studies involving 264 patients with spasticity were dry mouth, somnolence/sedation, asthenia (weakness, fatigue and/or tiredness), and dizziness. Three-quarters of the patients rated the reactions as mild to moderate and one-quarter of the patients rated the reactions as being severe. These adverse reactions appeared to be dose related. Table 1 lists adverse reactions that were reported in greater than 2% of patients in three multiple dose, placebo-controlled studies who received tizanidine where the frequency in the tizanidine group was greater than the placebo group. Table 1: Multiple Dose, Placebo-Controlled Studies - Adverse Reactions Reported in >2% of Patients Treated with Tizanidine Tablets and Incidence Greater than Placebo Adverse Reaction Placebo N = 261 % Tizanidine Tablet N = 264 % Dry mouth 10 49 Somnolence 10 48 Asthenia * 16 41 Dizziness 4 16 UTI 7 10 Infection 5 6 Constipation 1 4 Liver test abnormality 2 6 Vomiting 0 3 Speech disorder 0 3 Amblyopia (blurred vision) <1 3 Urinary frequency 2 3 Flu syndrome 2 3 Dyskinesia 0 3 Nervousness <1 3 Pharyngitis 1 3 Rhinitis 2 3 * includes weakness, fatigue, and/or tiredness In the single dose, placebo-controlled study involving 142 patients with spasticity due to multiple sclerosis (Study 1) [ see Clinical Studies (14) ] , the patients were specifically asked if they had experienced any of the four most common adverse reactions: dry mouth, somnolence (drowsiness), asthenia (weakness, fatigue and/or tiredness), and dizziness. In addition, hypotension and bradycardia were observed. The occurrence of these reactions is summarized in Table 2. Other events were, in general, reported at a rate of 2% or less. Table2:SingleDose , Placebo-ControlledStudy—CommonAdverseReactionsReported Adverse Reaction Placebo N = 48 % Tizanidine Tablet , 8 mg , N = 45 % Tizanidine Tablet , 16 mg , N = 49 % Somnolence 31 78 92 Dry mouth 35 76 88 Asthenia * 40 67 78 Dizziness 4 22 45 Hypotension 0 16 33 Bradycardia 0 2 10 includes weakness, fatigue, and/or tiredness 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of tizanidine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac Disorders: Ventricular tachycardia, decreased blood pressure Hepatobiliary Disorders: Hepatotoxicity [see Warnings and Precautions (5.2) ] , hepatitis Musculoskeletal and Connective Tissue Disorders: arthralgia Nervous System Disorders: Convulsion, paresthesia, tremor, muscle spasms Psychiatric Disorders: Hallucinations [see Warnings and Precautions (5.4) ], depression Skin and Subcutaneous Tissue Disorders: Stevens Johnson Syndrome, anaphylactic reaction [see Warnings and Precautions (5.5) ] , exfoliative dermatitis, rash

Moderate or weak CYP1A2 inhibitors: avoid concomitant use; may cause hypotension, bradycardia, or excessive drowsiness; if concomitant use is necessary and adverse reactions occur, reduce tizanidine dosage or discontinue. ( 7.2 , 12.3 ) 7.1 Strong CYP1A2 Inhibitors Concomitant use of tizanidine with strong cytochrome P450 1A2 (CYP1A2) inhibitors (e.g., fluvoxamine, ciprofloxacin) is contraindicated. Changes in pharmacokinetics of tizanidine when administered with a strong CYP1A2 inhibitor resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment [see Contraindications (4) and Clinical Pharmacology (12.3) ]. 7.2 Moderate or Weak CYP1A2 Inhibitors Concomitant use of tizanidine with moderate or weak CYP1A2 inhibitors (e.g., zileuton, antiarrhythmics [amiodarone, mexiletine, propafenone, and verapamil], cimetidine, famotidine, oral contraceptives, acyclovir, and ticlopidine) should be avoided. If concomitant use is clinically necessary, and adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce tizanidine dosage or discontinue tizanidine therapy [see Clinical Pharmacology (12.3) ]. 7.3 Oral Contraceptives Concomitant use of tizanidine with oral contraceptives is not recommended. However, if concomitant use is clinically necessary and adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce or discontinue tizanidine therapy [see Clinical Pharmacology (12.3) ]. 7.4 Alcohol and Other CNS Depressants Alcohol increases the exposure of tizanidine after administration of tizanidine. This was associated with an increase in adverse reactions of tizanidine. Concomitant use of tizanidine with CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) may cause additive CNS depressant effects, including sedation. Monitor patients who take tizanidine with another CNS depressant for symptoms of excess sedation [see Clinical Pharmacology (12.3) ]. 7.5 a 2 -Adrenergic Agonists Concomitant use of tizanidine with other α 2 -adrenergic agonists is not recommended because hypotensive effects may be cumulative [ see Warnings and Precautions (5.1) ]. 7.6 Antihypertensive Medications Concomitant use of tizanidine with antihypertensive medications may cause additive hypotensive effects [see Warnings and Precautions (5.1) ] . Monitor patients who take tizanidine with antihypertensive medications for hypotension.